Pharmacology of H 394/84, a dihydropyridine neuropeptide Y Y1 receptor antagonist, in vivo

Malmström, Rickard E.; Balmér, Karin; Weilitz, Jessika; Nordlander, Margareta; Sjölander, May

doi:10.1016/s0014-2999(01)00919-0

Cited by 15 publications

(9 citation statements)

References 18 publications

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“…For example, the YI-selective antagonists SRI20819A (109), BIBP3226 (110; Fig. 1), BIB03304 (111), and H394/ 84 inhibit NPY-induced vasoconstriction in a variety of species (106,109,112,113). Interestingly, the centrally in-duced vascular effects of NPY (reduced blood pressure and heart rate) are also signaled mainly through YI (64), as are many of the psychological functions of NPY, such as decreased anxiety and depression (114)(115)(116)(117)(118).…”

Section: Receptors For the Npy Family Of Peptidesmentioning

confidence: 99%

Recent Developments in Our Understanding of the Physiological Role of PP-Fold Peptide Receptor Subtypes

Berglund

Hipskind

Gehlert

2003

Exp Biol Med (Maywood)

241

174

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The three peptides pancreatic polypeptide (PP), peptide YY (PYY), and neuropeptide Y (NPY) share a similar structure known as the PP-fold. There are four known human G-protein coupled receptors for the PP-fold peptides, namely Y1, Y2, Y4, and Y5, each of them being able to bind at least two of the three endogenous ligands. All three peptides are found in the circulation acting as hormones. Although NPY is only released from neurons, PYY and PP are primarily found in endocrine cells in the gut, where they exert such effects as inhibition of gall bladder secretion, gut motility, and pancreatic secretion. However, when PYY is administered in an experimental setting to animals, cloned receptors, or tissue preparations, it can mimic the effects of NPY in essentially all studies, making it difficult to study the effects of PP-fold peptides and to delineate what receptor and peptide accounts for a particular effect. Initial studies with transgenic animals confirmed the well-established action of NPY on metabolism, food-intake, vascular systems, memory, mood, neuronal excitability, and reproduction. More recently, using transgenic techniques and novel antagonists for the Y1, Y2, and Y5 receptors, NPY has been found to be a key player in the regulation of ethanol consumption and neuronal development.

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Section: Receptors For the Npy Family Of Peptidesmentioning

confidence: 99%

Recent Developments in Our Understanding of the Physiological Role of PP-Fold Peptide Receptor Subtypes

Berglund

Hipskind

Gehlert

2003

Exp Biol Med (Maywood)

241

174

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“…Infusion or bolus injection of NPY moderately increases MAP [ 8 , 10 , 33 , 34 , 35 , 36 , 37 ], lowers HR [ 34 ], lowers RBF and increases RVR [ 8 , 10 , 11 , 33 , 34 , 36 , 37 , 38 ]. While most agents lowering RBF also decrease diuresis and natriuresis [ 3 ], infusion of NPY markedly increases diuresis and natriuresis [ 8 , 33 , 34 , 35 , 36 , 37 ] but does not affect CCR [ 8 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…These findings were confirmed in the present study. Studies based on subtype-selective peptide analogs of NPY and on the Y 1 -selective non-peptide antagonist BIBP 3226 have established that reductions of RBF occur via Y 1 receptors [ 11 , 28 , 33 , 38 ], whereas enhancements of diuresis and natriuresis occur via Y 5 receptors [ 33 ]. The renovascular and tubular effects of NPY are also discriminated by the NPY receptor antagonist D-myo-inositol 1,2,6-triphosphate [ 8 ] and the cyclooxygenase inhibitor indomethacin [ 36 ], with the former mainly inhibiting the renovascular and the latter mainly the tubular effects of NPY.…”

Section: Discussionmentioning

confidence: 99%

Effects of Nifedipine on Renal and Cardiovascular Responses to Neuropeptide Y in Anesthetized Rats

Bischoff¹,

Stickan-Verfürth²,

Michel

2021

Molecules

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Neuropeptide Y (NPY) acts via multiple receptor subtypes termed Y1, Y2 and Y5. While Y1 receptor-mediated effects, e.g., in the vasculature, are often sensitive to inhibitors of L-type Ca2+ channels such as nifedipine, little is known about the role of such channels in Y5-mediated effects such as diuresis and natriuresis. Therefore, we explored whether nifedipine affects NPY-induced diuresis and natriuresis. After pre-treatment with nifedipine or vehicle, anesthetized rats received infusions or bolus injections of NPY. Infusion NPY (1 µg/kg/min) increased diuresis and natriuresis, and this was attenuated by intraperitoneal injection of nifedipine (3 µg/kg). Concomitant decreases in heart rate and reductions of renal blood flow were not attenuated by nifedipine. Bolus injections of NPY (0.3, 1, 3, 10 and 30 μg/kg) dose-dependently increased mean arterial pressure and renovascular vascular resistance; only the higher dose of nifedipine (100 μg/kg/min i.v.) moderately inhibited these effects. We conclude that Y5-mediated diuresis and natriuresis are more sensitive to inhibition by nifedipine than Y1-mediated renovascular effects. Whether this reflects a general sensitivity of Y5 receptor-mediated responses or is specific for diuresis and natriuresis remains to be investigated.

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“…On the other hand, presynaptic Ca 2+ channels, which were functionally blocked by w -CTX, were partially reserved by NPY Y2-receptor inhibition. Recently, it has been reported that the dihydropyridine compound H394 /84 is a highly selective NPY Y1-receptor antagonist (14), although the dihydropyridine compound has in general Ca 2+ inward current inhibitory properties (15). Since it is well recognized that a dihydropyridine compound modifies the reactivity to Ca 2+ channels, NPY receptors may partially participate in the Ca 2+ channel reactivity.…”

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confidence: 99%

Antagonistic Interaction Between BIIE 0246, a Neuropeptide Y Y2-Receptor Antagonist, and ωy-Conotoxin GVIA, a Ca2+ Channel Antagonist, in Presynaptic Transmitter Releases in Dog Splenic Arteries

Yang

Chiba

2002

Japanese Journal of Pharmacology

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ABSTRACT-Isolated dog splenic arteries were perfused with Krebs-Henseleit solution at 37°C, using the cannula inserting method. Periarterial nerve electrical stimulation (10-V amplitude; 1-ms duration; 30-s trains of pulses; 1, 4 and 10 Hz) readily caused double peaked vasoconstrictions, i.e., 1st peaked response was mostly inhibited by a,b -methylene ATP and the 2nd one, by prazosin. These responses were consistently inhibited by w -conotoxin GVIA (w -CTX), whereas they were facilitated by BIIE 0246, a neuropeptide Y (NPY) Y 2 -receptor antagonist. The w -CTX-induced blocking effects of transmitter release were significantly antagonized by BIIE 0246. It is possible that the NPY Y 2 receptor activity may partially be linked to presynaptic Ca 2+ channels.Keywords: Dog splenic artery, Perivascular nerve electrical stimulation, a -Adrenoceptor It has been well recognized that neuropeptide Y (NPY) presynaptically inhibits a release of neurotransmitters via activation of NPY Y 2 receptors, whereas NPY postsynaptically facilitates transmitter-induced effect via Y1 receptors in the rat vas deferens and in the dog splenic artery (1 -6). Previously, we demonstrated in the isolated canine splenic artery that double peaked responses (two phases of the vasoconstriction) were consistently induced by periarterial nerve electrical stimulation (PNS) with the condition of 30-s trains of pulses at 10-V amplitude, 1-ms duration in a frequency-related manner; i.e., the 1st phase response might mainly contain a purinergic component and the 2nd response, mostly an adrenergic one (7,8). The inhibition of the double-peaked responses by NPY Y2-receptoractivation seems to be different from that by tetrodotoxin (TTX), a potent sodium inward current inhibitor, because the double-peaked vasoconstrictions were inhibited in parallel by Y 2 receptor activation, but TTX blocked only the 2nd peaked one in a small dose (4, 9). On the other hand, an N-type Ca 2+ channel antagonist, w -conotoxin GVIA (w -CTX), which specifically blocks N-type Ca 2+ channels, caused a parallel inhibition of the double-peaked vasoconstrictions (10). The Ca 2+ entry through neuronal Ca 2+ channels is a key step in neurotransmitter release, and the cellular mechanisms that regulate the activities of presynaptic Ca 2+ channels are still widely investigated (11). Thus, we considered that Y 2 receptor-activated inhibitory effects may be related to presynaptic regulating mechanisms of Ca 2+ channels. In the present study, we made an attempt to investigate the effects of a selective NPY Y2-receptor antagonist, BIIE 0246, on Ca 2+ channeldependent release of neurotransmitters.Mongrel dogs of either sex, weighing 12 to 15 kg, were anesthetized with sodium pentobarbital (30 mg /kg, i.v.). The heparinized dogs (200 units /kg, i.v.) were killed by rapid exsanguination from the right femoral artery. The main branches of the splenic artery were isolated, and side branches of the artery were tied with silk threads. Then, the artery (1 -1.2 mm in outer diameter) was cut into segmen...

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Pharmacology of H 394/84, a dihydropyridine neuropeptide Y Y1 receptor antagonist, in vivo

Cited by 15 publications

References 18 publications

Recent Developments in Our Understanding of the Physiological Role of PP-Fold Peptide Receptor Subtypes

Recent Developments in Our Understanding of the Physiological Role of PP-Fold Peptide Receptor Subtypes

Effects of Nifedipine on Renal and Cardiovascular Responses to Neuropeptide Y in Anesthetized Rats

Antagonistic Interaction Between BIIE 0246, a Neuropeptide Y Y2-Receptor Antagonist, and ωy-Conotoxin GVIA, a Ca2+ Channel Antagonist, in Presynaptic Transmitter Releases in Dog Splenic Arteries

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